PROJECT SUMMARYABSTRACT Subcortical ischemic vascular disease (SIVD), which is the major form of vascular cognitive impairment (VCI), is common in the elderly due to the prevalence of small vessel disease secondary to hypertension, diabetes, and the metabolic syndrome. There is strong evidence that the white matter damage in SIVD is related to a neuroinflammatory response, and NIH has emphasized the need for animal models to be used to develop new treatments. The long-term goal is to use a novel animal model of white matter damage in spontaneously hypertensive/stroke prone rats (SHR/SP) to define the pathophysiology and to test drugs that could be translated into clinical trials. The SHR/SP animal model was developed by the PI during the prior grant, and is based on strong preliminary data, showing the major role of matrix metalloproteinases (MMPs) that are induced by hypoxia. The animal model for SIVD uses SHR/SP rats that are fed a Japanese Permissive Diet (JPD) at 12 weeks of age and subjected to a unilateral carotid artery occlusion (UCAO). The central hypothesis is that hypertension induces hypoxia in the deep white matter, driving a molecular cascade that begins with production of hypoxia inducible factor-1 (HIF-1) and leads to expression of MMPs, disruption of the BBB, vasogenic edema, oligodendrocyte death, and ultimately behavioral dysfunction. The rationale of the proposed research is to determine the factors involved in the progressive damage to the white matter, and to use that understanding to test potential treatments. This hypothesis will be tested with three specific aims: 1) Determine the role of hypoxia in white matter damage in chronically hypertensive rats by using electron paramagnetic resonance (EPR) to measure ptO2 with lithium phthalocyanine (LiPc) microcrystals implanted stereotactically into the corpus callosum, and to correlate the impact of hypoxia on the structural changes in white matter with multimodal MRI; 2) Determine the molecular events occurring in the hypoxic white matter that lead to oligodendrocyte death and to determine the relationship of white matter ptO2 to damage to the cerebral capillaries; and 3) To test potential therapeutic agents to reduce white matter damage and improve behavior by interfering with the neuroinflammatory response that leads to oligodendrocyte death. EPR/MRI will be used to noninvasively monitor injury and recovery along with biochemical and behavioral end-points. These studies are innovative because they use EPR to monitor oxygen and multimodal MRI to show white matter damage along with biochemical and behavioral testing to completely characterize the mechanisms of damage, and to allow the course of the injury to be followed in the same animal over several months. The significance is that this novel animal model for VCI provides a means to test potential therapies for a common dementing illness in the elderly and that results from these studies could be translated into clinical trials.